Continuing Education Activity

Diltiazem is an oral and parenteral non-dihydropyridine calcium channel blocker. It is used in many clinical scenarios as an antihypertensive, anti-arrhythmic, and anti-anginal. FDA-approved indications include atrial arrhythmia, hypertension, paroxysmal supraventricular tachycardia, and chronic stable angina. Diltiazem also has numerous off-label indications for migraine prophylaxis, anal fissures, and pulmonary hypertension. This activity will highlight the mechanism of action, adverse event profile, approved and off-label uses, dosing, pharmacodynamics, pharmacokinetics, relevant diltiazem interactions, and monitoring of patients treated with diltiazem. It also emphasizes the pertinent interprofessional team members' role when prescribing diltiazem for any of its intended indications.

Objectives:

• Explain the mechanisms of action for diltiazem.
• Identify the approved and off-label indications for diltiazem use.
• Review the adverse events for diltiazem therapy.
• Outline the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients when using diltiazem.

Indications

Diltiazem is an oral and parenteral non-dihydropyridine calcium channel blocker. It is useful in many clinical scenarios as an antihypertensive, anti-arrhythmic, and anti-anginal agent.[1] 

FDA-approved Indications

• Atrial arrhythmia, including atrial fibrillation with the rapid ventricular rate (RVR)[2]

• Hypertension

• Paroxysmal supraventricular tachycardia

• Chronic stable angina

• Angina Due to Coronary Artery Spasm( Prinzmetal's or variant angina)[3]

Diltiazem also has utility in numerous off-label indications. A select few are listed below.

Non-FDA-approved Indications

• Anal fissures[4]

• Migraine prophylaxis[5]

• Pulmonary hypertension(Group 1 Pulmonary hypertension patients with positive vasoreactivity test)[6][7]

Mechanism of Action

Diltiazem is a non-dihydropyridine calcium channel blocker (CCB). Therapeutic effects occur through various mechanisms. Primarily, diltiazem inhibits the inflow of calcium ions into the cardiac muscle during depolarization. Reduced intracellular calcium concentrations increase smooth muscle relaxation, resulting in arterial vasodilation and decreased blood pressure. 

Hypertension

• Diltiazem primarily produces its antihypertensive effect by relaxing the vascular smooth muscle and decreasing peripheral vascular resistance. The magnitude of blood pressure reduction is related to hypertension; thus, hypertensive individuals experience an antihypertensive effect, whereas there is only a modest fall in blood pressure in normotensives.

Atrial Arrhythmia/Paroxysmal Supraventricular Tachycardia

• Diltiazem is a negative inotrope (decreased force) and negative chronotrope (reduced rate). Along with coronary artery vasodilation, the combination decreases myocardial oxygen demand resulting in decreased heart rate.

Angina

• Diltiazem has been shown to increase exercise tolerance, probably due to its ability to reduce myocardial oxygen demand. This is accomplished via reductions in heart rate and blood pressure at submaximal and maximal workloads. Diltiazem is a potent dilator of coronary arteries, both epicardial and subendocardial.[8]

Pharmacokinetics

Absorption: Diltiazem is well absorbed from the GIT and undergoes extensive first-pass metabolism; resultant bioavailability is approximately 40%. The immediate-release diltiazem tablet has an onset of action of 30 to 60 minutes.[9] 

Distribution: Diltiazem is 70% to 80% bound to plasma proteins. 

Metabolism: Diltiazem is metabolized by the cytochrome P450 system and is an inhibitor of CYP3A4, which can lead to drug-drug interactions. Desacetyl diltiazem, the metabolite of diltiazem, also contributes to coronary vasodilatation.[10]

Excretion: The plasma elimination half-life following drug administration is about 3.0 to 4.5 hours. Diltiazem undergoes extensive metabolism in which 2% to 4% of the unchanged drug appears in the urine.

Administration

In the United States, diltiazem is FDA-approved as an oral immediate-release, extended-release, controlled-release (CD), and intravenous formulation. There are numerous brand names for oral diltiazem (capsules and tablets), and available strengths include 30 mg, 60 mg, 90 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, and 420 mg. Compounded topical preparations of diltiazem are used off-label.[11][12] Review the package insert for the formulation by brand name because pharmacokinetics vary significantly between different brands. 

Diltiazem may be confused with diazepam. The use of tall-man lettering is advised to avoid this medication error as it poses a significant threat to patient safety. Hence FDA and ISMP (institute of safe medical practices) have provided the name of these sound-alike look-alike drugs to avoid potential medical errors.[13][14]

The following represent the dosing variances by condition using generic names under various trade names.

Recommended Dosages

Hypertension

• Diltiazem hydrochloride (various brands)
  • Initial dose: 180 mg to 240 mg once daily
  • Maximum dose: 480 mg once daily
• Diltiazem HCl (various brands)
  • Initial dose: 120 mg to 240 mg once daily
  • Maximum dose: 540 mg once daily
• Diltiazem HCl extended-release (various brands)
  • Initial dose: 180 mg to 240 mg once daily
  • Maximum dose: 540 mg once daily

 Chronic Stable Angina

• Diltiazem hydrochloride (various brands)
  • Initial dose: 30 mg four times daily*
• Diltiazem HCl (various brands)
  • Initial dose: 120 mg to 180 mg once daily
  • Maximum dose: 480 mg once daily
• Diltiazem HCl (various brands)
  • Initial dose: 120 mg to 180 mg once daily
  • Maximum dose: 540 mg once daily
• Diltiazem HCl extended-release (various brands)*
  • Initial dose: 180 mg once daily
• Diltiazem HCl extended-release (various brands)
  • Initial dose: 120 mg once daily
  • Maximum dose: 480 mg once daily

Atrial Arrhythmia/Paroxysmal Supraventricular Tachycardia 

• Initial dose: IV bolus 0.25 mg/kg ABW(adjusted body weight) IV over 2 minutes
  • If needed, repeat the dose at 0.35 mg/kg ABW IV after 15 minutes
• Maintenance dose: IV continuous infusion 10mg/hr
  • Increase dose at 5mg/hr to max 15mg/hr
  • Max infusion time is 24 hours 

Renal Impairment

• No dose adjustment is necessary.

Hepatic Impairment

• No dose adjustment is likely needed for mild-moderate hepatic impairment, but diltiazem is extensively metabolized in the liver. Consequently, use with caution in hepatic impairment.[3]

Pregnancy Considerations

• Diltiazem is teratogenic in animals, and only limited human data exist; thus, its use is only recommended in pregnancy if the potential benefit justifies the potential risk to the fetus.[15]

Breastfeeding Considerations

• Diltiazem is excreted in human milk. Based on the current data, the amounts of diltiazem ingested by the infant are small. However, due to serious adverse reactions, if diltiazem is deemed essential, the clinician should suggest an alternative method of infant feeding.[16]

Adverse Effects

• Common adverse effects of diltiazem therapy include peripheral edema, bradycardia, dizziness, headache, and fatigue.[17]

• Severe adverse effects include congestive heart failure, myocardial infarction, and hepatotoxicity.[3]

• Diltiazem is indicated for treating arrhythmias and, consequently, has the potential to worsen or create new arrhythmias such as extrasystole and AV block.[18]

• Diltiazem is extensively metabolized through the CYP450 system and requires careful medication profile review. Concomitant use alongside potent CYP450 inhibitors may increase diltiazem concentrations leading to adverse effects even at clinically recommended doses.[19]

• Concurrent administration with agents that slow cardiac conduction can further potentiate adverse effects like AV block or bradycardia.[20]

• Diltiazem-associated photo-distributed hyperpigmentation has been described in case reports.[21]

• Drug-Drug Interactions: Beta-blockers and diltiazem interaction may lead to bradyarrhythmias. [22] A recent drug-drug interaction study has identified a fatality resulting from diltiazem-ibrutinib interaction. Diltiazem is a moderate inhibitor of CYP3A4, and ibrutinib is a substrate of this CYP3A4; concurrent administration for an extended time decreases ibrutinib clearance and results in cardiotoxicity.[23] Diltiazem is also a P-glycoprotein inhibitor;  hence there is an increased bleeding risk associated with direct oral anticoagulants (DOACs) like dabigatran or apixaban concomitantly with the  P-glycoprotein inhibitor diltiazem.[24]

Contraindications

• Sick sinus syndrome except in the presence of a functioning ventricular pacemaker

• Severe hypotension(SBP<90 mm hg)

• Documented hypersensitivity to the drug

• Acute myocardial infarction and pulmonary congestion

• Concurrent administration of intravenous beta-blockers

• Wide complex ventricular tachycardia[25]

• Atrial fibrillation or flutter associated with an accessory bypass tract (i.e., Wolff-Parkinson-White syndrome)[26]

• Second- or third-degree AV block except in the presence of a functioning ventricular pacemaker[18]

• Cardiogenic shock[27]

• According to ACC/AHA 2022 guidelines, in patients with HFrEF(heart failure with reduced ejection fraction) after acute myocardial infarction, diltiazem is associated with a higher risk of recurrent HF.[28]

• Alcohol increases the rate of absorption of diltiazem hydrochloride. Alcohol increases the rate and extent of exposure to diltiazem controlled-release (CD) formulation and is associated with dose-related adverse reactions. Advise patients to avoid simultaneous consumption of alcohol with diltiazem CD.

Monitoring

Therapeutic monitoring includes periodic blood pressure assessments, heart rate, and electrocardiograms. When treating hypertension and arrhythmias, objective findings assess the therapy's efficacy. In contrast, subjective findings, such as a patient's frequency and severity of chest pain, are used to evaluate effectiveness when treating chronic angina.

A comprehensive metabolic panel is also performed at baseline to track potential changes in electrolytes and kidney and liver function.

Additional monitoring is required when using diltiazem parenterally. When treating arrhythmias, an IV bolus is administered over two minutes. Continuous blood pressure and ECG monitoring are necessary during bolus administration. 

For the treatment of hypertension during pregnancy, recommendations state that using an alternative agent, since diltiazem has shown adverse fetal effects in animal studies. If a patient is controlled on diltiazem to treat hypertrophic cardiomyopathy, diltiazem therapy may continue, but additional fetal monitoring is required.[15]

Similarly, serum digoxin levels should be monitored with concurrent administration of diltiazem. Clinicians should monitor apixaban anti-Xa assay or heparin anti-Xa assay to decide if patients require dose adjustment to reduce adverse events in patients prescribed apixaban and concomitant p-glycoprotein and CYP3A4 inhibitors like diltiazem with statins.[29]

Toxicity

Diltiazem is available in many dosage forms and strengths, making it imperative to be cautious when prescribing, dispensing, and administering this medication. There have been reports of diltiazem overdose in amounts ranging from <1 g to 18 g. In cases with the known outcome, most patients recovered, and in cases with a fatal outcome, the majority involved multiple drug ingestion. 

Clinical Features 

• Profound bradycardia

• Dizziness

• End organ dysfunction 

• Hypotension

• AV block

• Cardiac failure

• Cardiac arrest

Management

• Treat according to ACLS protocol for arrhythmias and hypotension.[30]

• Whole bowel irrigation for gastrointestinal decontamination[31]

• Administer IV calcium gluconate or calcium chloride.[32]

• Administer IV atropine (0.60 to 1.0 mg) for bradycardia.[33]

• IV glucagon enhances intracellular levels of cyclic adenosine monophosphate and increases heart rate.[34]

• Severe toxicity may respond to hyperinsulinemia/euglycemia therapy(HIET).[35] 

• Lipid emulsion therapy in significant cardiotoxicity.[36]

• Transvenous pacemaker to assist with electrical conduction. If there are no contraindications, an intra-aortic balloon pump can be deployed.[37]

• Extracorporeal membrane oxygenation is used for  Massive diltiazem overdose.[38]

• CCBs, including diltiazem, are extremely protein-bound; consequently, extracorporeal removal by hemodialysis is ineffective.[39]

• Administer vasopressors and inotropic agents (e.g., dopamine or norepinephrine) for severe hypotension and cardiac failure.[40]

• The use of vasopressors is common in patients with diltiazem overdose and is associated with promising clinical outcomes.[40]

Enhancing Healthcare Team Outcomes

Diltiazem has been widely used in practice for many clinical indications. Proper dosage and frequency are essential to enhance patient care and improve outcomes. Diltiazem possesses negative inotropic effects and is generally avoided in patients with congestive heart failure, and diltiazem is also on the Beers Criteria.[41] These factors highlight the importance of avoiding diltiazem in patients with heart failure, especially in the elderly, due to drug interactions and exacerbation of heart failure.[42] According to the study, older adults with hypertension who are prescribed calcium channel blockers, including diltiazem, are dispensed a loop diuretic at higher rates due to peripheral edema. This is an example of prescribing cascade; clinicians should re-assess the patient before prescribing a diuretic to treat peripheral edema.[43] [level 3]

Ideally, Clinicians should verify drug, dose, and patient factors before administration. For example, one common error with diltiazem therapy is an incorrect dose administered to the patient. Double-checking doses can help ensure the patient receives appropriate therapeutic management in inpatient and outpatient settings. Pharmacists, nurses, and other providers should also check for potential drug interactions with other medications of the patient's profile. For example, diltiazem is available in many brand names with differing recommended dosages and maximum daily doses; this vigilance will limit drug interactions and incorrect dosing. Nursing staff should monitor for clinical improvement and any adverse drug reactions and inform the clinicians in case of any inconsistency. If the pharmacist or nurse suspects anything is amiss, they should contact the prescriber immediately.

In overdose, triage nurses and emergency department physicians should quickly stabilize the patient. Critical care physician supervision is necessary for severe hypotension and cardiac failure. IABP insertion requires cardiac consultation. Obtain the latest information by contacting the poison control center (800-222-1222) in the United States. As illustrated above, clinicians (MDs, DOs, NPs, PAs), specialists, nurses, pharmacists, and other healthcare providers are involved in taking care of the patient. Hence it is vital to communicate and work collaboratively for better patient outcomes related to diltiazem therapy. An interprofessional team approach involving all the providers would maximize efficacy and minimize adverse drug reactions translating to optimal patient outcomes with minimum adverse drug reactions. [Level 5]